Synthesis of non-C2-symmetric bisphosphine ligands as catalysts for asymmetric hydrogenation

ABSTRACT

Non-C2-symmetric bisphospholane ligands and methods for their preparation are described. Use of metal/non-C2-symmetric bisphospholane complexes to catalyze asymmetric transformation reactions to provide high enantiomeric excesses of formed compounds is also described.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 60/277,125, filed Mar. 19, 2001.

FIELD OF THE INVENTION

This invention relates to non-C₂-symmetric bisphosphine (BisP) ligandsand a method for their preparation. In addition, this invention relatesto forming metal/bisphosphine complexes that catalyze asymmetrictransformation reactions to generate high enantiomeric excesses offormed compounds. The invention also relates to a method for preparingBisP.

BACKGROUND OF THE INVENTION

A growing trend in the pharmaceutical industry is to market chiral drugsin enantiomerically pure form to provide desired positive effects inhumans. Production of enantiomerically pure compounds is important forseveral reasons. First, one enantiomer often provides a desiredbiological function through interactions with natural binding sites, butanother enantiomer typically does not have the same function or effect.Further, it is possible that one enantiomer has harmful side effects,while another enantiomer provides a desired positive biologicalactivity. To meet this demand for chiral drugs, many approaches forobtaining enantiomerically pure compounds have been explored such asdiastereomeric resolution, structural modification of naturallyoccurring chiral compounds, asymmetric catalysis using synthetic chiralcatalysts and enzymes, and the separation of enantiomers using simulatedmoving bed (SMB) technology.

Asymmetric catalysis is often the most efficient method for thesynthesis of enantiomerically enriched compounds because a small amountof a chiral catalyst can be used to produce a large quantity of a chiraltarget molecule. Over the last two decades, more than a half-dozencommercial industrial processes have been developed that use asymmetriccatalysis as the key step in the production of enantiomerically purecompounds with a tremendous effort focused on developing new asymmetriccatalysts for these reactions (Morrison J. D., ed. Asymmetric Synthesis,New York: Academic Press, 1985:5; Bosnich B., ed. Asymmetric Catalysis,Dordrecht, Netherlands: Martinus Nijhoff Publishers, 1986; Brunner H.Synthesis, 1988:645; Noyori R., Kitamura M. In Scheffold R., ed. ModernSynthetic Methods, Berlin Hedelberg: Springer-Verlag, 1989;5: 115;Nugent W. A., RajanBabu T. V., Burk M. J. Science, 1993;259:479; OjimaI., ed. Catalytic Asymmetric Synthesis, New York: VCH, 1993; Noyori R.Asymmetric Catalysis In Organic Synthesis, New York: John Wiley & Sons,Inc, 1994).

Chiral phosphine ligands have played a significant role in thedevelopment of novel transition metal catalyzed asymmetric reactions toproduce enantiomeric excess of compounds with desired activities. Thefirst successful attempts at asymmetric hydrogenation of enamidesubstrates were accomplished in the late 1970s using chiralbisphosphines as transition metal ligands (Vineyard B. D., Knowles W.S., Sabacky M. J., Bachman G. L., Weinkauff D. J. J. Am. Chem. Soc.1977;99(18):5946-52; Knowles W. S., Sabacky M. J., Vineyard B. D.,Weinkauff D. J. J. Am. Chem. Soc. 1975;97(9):2567-8).

Since these first published reports, there has been an explosion ofresearch geared toward the synthesis of new chiral bisphosphine ligandsfor asymmetric hydrogenations and other chiral catalytic transformations(Ojima I., ed. Catalytic Asymmetric Synthesis, New York: VCH Publishers,Inc, 1993; Ager D. J., ed. Handbook of Clinical Chemicals, MarcelDekker, Inc, 1999). Highly selective rigid chiral phospholane ligandshave been used to facilitate these asymmetric reactions. For example,phospholane ligands are used in the asymmetric hydrogenation of enamidesubstrates and other chiral catalytic transformations.

BPE, Duphos, and BisP ligands are some of the most efficient and broadlyuseful ligands developed for asymmetric hydrogenation to date (Burk M.J. Chemtracts 1998; 1(1 1):787-802 (CODEN: CHEMFW ISSN:1431-9268. CAN130:38423; AN 1998:698087 CAPLUS); Burk M. J., Bienewald F., Harris M.,Zanotti-Gerosa A. Angew Chem., Int. Ed. 1998;37(13/14):1931-1933; Burk,M. J., Casy G., Johnson N. B. J. Org. Chem. 1998;63(18):6084-6085; BurkM. J., Kalberg C. S., Pizzano A. J. Am. Chem. Soc.1998;120(18):4345-4353; Burk M. J., Harper T., Gregory P., Kalberg C. S.J. An. Chem. Soc. 1995;117(15):4423-4424; Burk M. J., Feaster J. E.,Nugent W. A., Harlow R. L. J. Am. Chem. Soc. 1993;115(22):10125-10138;Nugent W. A., RajanBabu T. V., Burk M. J. Science (Washington, DC 1883-)1993;259(5094):479-483; Burk M. J., Feaster J. E., Harlow R. L.Tetrahedron: Asymmetry 1991;2(7):569-592; Burk M J. J. Am. Chem. Soc.1991;113(22):8518-8519; Imamoto T., Watanabe J., Wada Y., Masuda H.,Yamada H., Tsuruta H. et al. J. Am. Chem. Soc. 1998; 120(7):1635-1636;Zhu G, Cao P, Jiang Q, Zhang X. J. Am. Chem. Soc. 1997;119(7):1799-1800). For example, a Rhodium/Duphos complex can be used toselectively form (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, known aspregabalin, which is used as an anti-seizure drug. The S-enantiomer,which is produced in an enantiomeric excess, is preferred because itshows better anticonvulsant activity than the R-enantiomer (Yuen et al.,Bioorganic & Medicinal Chemistry Letters 1994;4:823).

The success of BPE, DuPhos, and BisP transition metal complexes inasymmetric hydrogenations is derived from many factors. For example,substrate to catalyst ratios of up to 50,000/1 have been demonstrated.Also, high rates of substrate conversion to product using low hydrogenpressures have been observed with catalysts made from these ligands.

BPE, Duphos, and BisP have shown high enantioselectivities in numerousasymmetric reactions. Improved reaction of BPE, Duphos, and BisP isattributed to, among other factors, rigidity in their C₂-symmetricstructure. If the spatial area of a metal/phosphine ligand structure,such as BisP, is divided into four quadrants, as shown in FIG. 1,alternating hindered and unhindered quadrants are formed.

This structural feature creates areas of hindrance in the BisP/metalcomplexes and produces desired stereochemical results in asymmetrichydrogenation reactions. However, there are a variety of reactions inwhich only modest enantioselectivity has been achieved with theseligands. While high selectivity has been observed in many reactionsusing these chiral diphosphine ligands, there are many reactions wherethese ligands are not very efficient in terms of activity andselectivity. Further, there are many disadvantages associated with theseligands, which limits their application.

For example, multiple chiral centers in these ligands increases thedifficulty in synthesis of these compounds. Further, the multiple chiralcenters could increase the cost associated with forming the ligands.

High enantioselectivities have been observed in asymmetric hydrogenationfor a narrow range of substrates, such as enamides, enol esters, andsuccinates. Many of these successful results have been obtained usingoptically pure C₂-symmetric rhodium-phosphine complexes as hydrogenationcatalysts. Therefore, C₂-symmetry has become a popular characteristic inthe design of chiral ligands that are used to make these complexes.Unique to the substrates for which asymmetric hydrogenation has beensuccessful is an olefin and a carbonyl group which are separated by oneatom. During asymmetric hydrogenation, the olefin and the carbonyl bindto the metal center in a well-defined conformation. This is thought tobe of consequence in an asymmetric hydrogenation.

C₂-symmetric bisphosphines, such as BisP, have been synthesized and usedin asymmetric catalysis, as shown in FIG. 2 (Imamoto, T., Watanabe J.,Wada Y., Masuda H., Yamada H., Tsuruta I-I., Matsukawa S., Yamaguchi K.J Am. Chem. Soc. 1998;120(7):1635-1636). A proton from one of the methylgroups of t-butyldimethyl phosphine is selectively deprotonated with achiral base, such as s-BuLi and (−)-sparteine, and then the resultinganion couples with itself in the presence of copper(II) chloride toprovide the bisphosphine borane protected ligand, in about 40% yieldand >99% enantiomeric excess after recrystallization. The rhodiumcomplex of BisP is known to give high enantiomeric excess inhydrogenation reactions for a variety of substrates. For instance, therhodium-BisP catalyst hydrogenates x-N-acetylmethylacrylate to produce98% enantiomeric excess (Imamoto T. et al., supra., 1998).

A drawback to the synthesis of the BisP ligand in FIG. 2 is that onlyone antipode of sparteine is available in nature, and therefore, onlyone enantiomer of the ligand (the S,S isomer) can be synthesized viathis route.

Basic research has been done by a variety of groups in the late 1970s onthe mechanism and origin of enantioselectivity of asymmetrichydrogenation reactions which result in high enantiomeric excess (AlcockN. W., Brown J. M.; Derome A. E., Lucy A. R. J. Chem. Soc. Chem. Comm.1985:575; Brown J. M., Chaloner P. A., Morris G. A. J. Chem. Soc. Chem.Comm. 1983:664; Halpern J. Science 1982;217,401; Brown J. M., ChalonerP. A. J. Chem. Soc. Chem. Comm. 1980;344). The 3-dimensional structureof a C₂-symmetric complex like the rhodium complex of BisP has fourquadrants that alternate hindered and unhindered, as shown in FIG. 1.

Ligand and metal/ligand complexes are needed that can further improvethe production of enantiomerically active forms of compounds. Thus,there is a need to develop methods for the production of and tosynthesize compounds that reduce the number of chiral centers on amolecule and through prohibitive substituents on the ligand improveenantioselectivity in asymmetric reactions.

SUMMARY OF THE INVENTION

The present invention provides for non-C₂-symmetric bisphosphineligands. Non-C₂ bisphosphine ligands when complexed with a metal, serveas catalysts in asymmetric hydrogenation reactions to formenantiomerically enriched compounds. One non-C₂-symmetric bisphosphineis represented by the general Formula I:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent; and

the Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl.

Another non-C₂-symmetric bisphosphine compound of present invention hasthe general Formula II:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent; and

each Y is independently halogen, alkyl, alkoxy, aryl, aryloxy, nitro,amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid, and n is aninteger from 0 to 4 equal to the number of unsubstituted aromatic ringcarbons.

Another aspect of the invention is directed to the method for formingP-chiral bisphosphine ligands. Compounds used as synthons during thesynthesis of non-C₂-symmetric bisphosphine ligands include compoundswith the Formulas III, IV, V, and VI:

wherein R is t-butyl, isopropyl, adamantyl, (1,1-dimethylpropane),(1,1-diethylbutane) c-C₅H₉, or c-C₆H₁₁; and Ms is mesylate.

Another aspect of the invention is directed to methods for formingnon-C₂-bisphosphine ligands. The methods include preparing compounds ofthe general structural Formulas I and II, as shown in FIG. 4-FIG. 12.

Another compound of the present invention has the general Formula VIII:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent;

a Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl;

M is a transition metal, an actinide, or a lanthanide; and

Z is BF₄, PF₆, SbF₆, OTf, or ClO₄.

Yet another aspect of the invention is directed to forming enantiomericexcesses of compounds catalyzed with the metal/non-C₂-symmetricbisphosphine complexes in asymmetric reactions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a spatial arrangement of a metal/phosphine ligand.

FIG. 2 shows representative schemes for preparing C₂-symmetricbisphosphines, such as BisP, and for using C₂-symmetric bisphosphines inasymmetric catalysis.

FIG. 3 shows schemes for preparing synthons that can be used to preparenon-C₂-symmetric borane-protected ligands.

FIG. 4 shows schemes for preparing non-C₂-symmetric ligands usingsynthon III.

FIG. 5 shows schemes for preparing non-C₂-symmetric ligands usingsynthon IV.

FIG. 6 shows schemes for preparing non-C₂-symmetric ligands usingsynthon V.

FIG. 7 shows schemes for preparing non-C₂-symmetric ligands usingsynthon VI.

FIG. 8 shows a scheme for preparing non-C₂-symmetric ligands usingsynthon VII.

FIG. 9 shows a scheme for preparing compounds of Formula Ia.

FIG. 10 shows a scheme for preparing compounds of Formula IIa.

FIG. 11 shows a scheme for preparing compounds of Formula Ib.

FIG. 12 shows a scheme for preparing another bisphosphine ligand.

FIG. 13 shows a scheme for removing borane groups from an intermediateligand to form a compound of Formula Ia.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is applicable to the synthesis of non-C₂-symmetricbisphosphine ligands for use in metal/non-C₂-symmetric bisphosphinecomplexes for asymmetric catalysis. In particular, the present inventionis directed to reacting the metal/non-C₂-symmetric bisphosphinecomplexes to produce enantiomeric excesses of compound in asymmetrichydrogenation syntheses. While the present invention is not so limited,an appreciation of various aspects of the invention will be gainedthrough a discussion of the examples provided below.

For the purpose of this application, the “corresponding enantiomer”means that if a compound includes a stereochemical configurationdesignated as R, the corresponding enantiomer is the S configuration. Ifa compound has an S configuration, the corresponding enantiomer is the Rconfiguration. If a compound has a stereochemical configuration of1R,2S, the “corresponding enantiomer” is the 1S,2R compound. Similarly,if a compound has an 1S,2R configuration, the “corresponding enantiomer”is the 1R,2S compound. If a P-chiral compound has an 1S,2Sconfiguration, the “corresponding enantiomer” is the 1R,2R compound. Ifa compound has an 1R,2R configuration, the “corresponding enantiomer” isthe 1S,2S compound.

For the purpose of this application, a high level of enantioselectivitymeans a hydrogenation that yields a product of greater than or equal toabout 80%, preferably, greater than or equal to about 90% enantiomericexcess (abbreviated e.e.).

Enantiomeric excess is defined as the ratio (%R−%S)/(%R+%S)×100, where%R is the percentage of R enantiomer and %S is the percentage of Senantiomer in a sample of optically active compound. For the purpose ofthis application, by a “compound with a high degree of enantiomericpurity,” or a “compound of high enantiomeric purity” is meant a compoundthat exhibits enantiomeric excess to the extent of greater than or equalto about 90%, preferably, greater than or equal to about 95%enantiomeric excess (abbreviated e.e.).

Non-C₂-Symmetric Bisphosphines

The present invention provides novel non-C₂-symmetric bisphosphinesubstituted compounds of the general Formula 1:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent; and

the Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl.

Another non-C₂-symmetric bisphosphine compound of present invention hasthe general Formula II:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent; and

each Y is independently halogen, alkyl, alkoxy, aryl, aryloxy, nitro,amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid, and n is aninteger from 0 to 4 equal to the number of unsubstituted aromatic ringcarbons.

The term “alkyl”, as used in this application, includes a straight orbranched saturated aliphatic hydrocarbon chain, such as, for example,methyl, ethyl, propyl, isopropyl (1-methylethyl), butyl, tert-butyl(1,1-dimethylethyl), and the like.

The term “aryl” group, as used in this application, includes an aromatichydrocarbon group, including fused aromatic rings, such as, for examplephenyl and naphthyl. Such groups may be unsubstituted or substituted onthe aromatic ring by, for example, an alkoxy group of 1 to 4 carbonatoms, an amino group, a hydroxy group, or an acetyloxy group.

The term “aralkyl” group, as used in this application, includes anaromatic hydrocarbon group, including fused aromatic rings, such as forexample, phenyl and naphthyl, bonded to an alkyl group with the alkylbonded to the phospholane ring. The aromatic hydrocarbon group may beunsubstituted or substituted (ring substituted aralkyl) by, for example,an alkoxy group of 1 to 4 carbon atoms, an amino group, a hydroxy group,or an acetyloxy group.

The term “LAH,” as used in this application, is defined as lithiumaluminum hydride.

Achiral phosphorous groups include, but are not limited to, thefollowing:

wherein R is t-butyl, isopropyl, adamantyl, (1,1-dimethylpropane),(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁.

Chiral phosphorous groups include, but are not limited to, the followingand their corresponding enantiomers:

wherein:

R is t-butyl, isopropyl, adamantyl, (1,1-dimethylpropane),(1,1-diethylbutane), c-C₅H₉, or c-C₆ H₁₁;

R₂ is methyl, ethyl, isopropyl, cyclohexyl, benzyl, a ring substitutedbenzyl, an aryl, or a ring substituted aryl; and

R₃ is OBn, OH, suiphonate, or hydrogen.

A preferred R group for the achiral phosphorous groups of compounds ofthe general Formula I is t-butyl. Examples of other preferrednon-C₂-synimetric bisphosphine ligands of the general Formula I include,but are not limited to, those compounds in which R is isopropyl,adamantyl, (1,1-dimethylpropane), (1,1-diethylbutane), c-C₅H₉, orc-C₆H₁₁ and their corresponding enantiomers.

The non-C₂-symmetric bisphosphine substituted compound,1-(di-tert-butyl-phosphanyl)-((R)-2-tert-butyl-methyl-phosphanyl)ethaneis represented by the Formula Ia:

wherein R is t-butyl. In other embodiments, R is isopropyl, adamantyl,(1,1-dimethylpropane), (1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁.

The non-C₂-symmetric bisphosphine substituted compound,1-((S)-2,2′-phosphanyl-1,1′-binaphthyl)-2-((R)-2-tert-butyl-methyl-phosphanyl)ethaneis represented by the Formula Ib:

wherein R is t-butyl.

The non-C₂-symmetric bisphosphine substituted compound,1-((R)-2-tert-butyl-methyl-phosphanyl)-2-((R,R)-2,5-dialkylphosphanyl)ethaneis represented by the Formula Ic:

wherein R is t-butyl, and R₂ is alkyl.

The non-C₂-symmetric bisphosphine substituted compound,1-((R)-2-tert-butyl-methyl-phosphanyl)-2-((R,R)-2,5-dialkylphosphanyl)benzeneis represented by the Formula IIa:

wherein R is t-butyl, and R₂ is alkyl.

Compounds of the general Formulas Ia, Ib, and Ic include thecorresponding enantiomer of the compound shown in the structuralformulas.

The bisphosphine compounds of Formula I and II of the present inventionare useful as transition metal ligands in asymmetric catalysis. The useof these ligands to form transition metal catalysts results in a highlevel of enantioselective and stereochemical control in the catalyzedhydrogenation of unsaturated substrates.

Compounds I and II include one to three chiral centers instead of thefour chiral centers that are found in molecules such as Duphos. Ligandsdisplaying the structural motif of Ia do not necessarily have to containbulky groups on phosphorous that are the same. In other words, as longas there are three sterically hindered quadrants in the metal-ligandcomplex, the desired effect in asymmetric transformations will beachieved.

Several intermediate synthon compounds can be used to formnon-C₂-symmetric compounds, such as those with the general Formula I.This invention further comprises the use or synthesis of synthons withthe Formulas III, IV, V, and VI:

wherein R is t-butyl, isopropyl, adamantyl, (1,1-dimethylpropane),(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁; and Ms is mesylate.

The above bisphospholane compounds of Formulas I, II, and theircorresponding enantiomers can be complexed with any of the transitionmetals as well as the lanthanides and actinides. Such complexes areformed by methods known in the art. Another compound of the presentinvention includes the metal/P-chiral phospholane complex with thegeneral structural Formula VIII and its corresponding enantiomer:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent;

a Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl;

M is a transition metal, an actinide, or a lanthanide; and

Z is BF₄, PF₆, SbF₆, OTf, or ClO₄.

Preferred transition metal complexes of the present invention are thoseincluding the above described preferred compounds complexed withrhodium.

Synthesis of non-C₂ Bisphosphines

The synthesis the non-C₂ borane-protected ligands can be formed throughsynthons that are formed as shown in FIG. 3. For the synthons shown R ist-butyl, isopropyl, adamantyl, (1,1)-dimethylpropane,(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁; and Ms is mesylate.

An additional synthon is a compound with the formula:

wherein R is t-butyl, isopropyl, adamantyl, (1,1)-dimethylpropane,(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁. The above synthons can be usedin a variety of reactions to form non-C₂-symmetric ligands as shown inFIG. 4-FIG. 8. In each of the schemes shown in FIG. 4-FIG. 8, R ist-butyl, isopropyl, adamantyl, (1,1)-dimethylpropane,(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁, and Ms is mesylate.

FIG. 9 shows a method of synthesis to compound Ia. In the scheme shownin FIG. 9, R is t-butyl, isopropyl, adamantyl, (1,1)-dimethylpropane,(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁; Ms is mesylate; R′ is methyl,benzyl, aryl, isopropyl; and R″ is H, methyl, benzyl, aryl, orisopropyl.

One method includes reacting (+/−)-tert-butyl-methyl-phosphane borane asa starting material. This primary phosphine is made via a one-potprocedure starting from dichloromethylphosphine, reacting withdimethylsulfide-borane, t-butyl magnesium chloride, and then LAH.(+/−)-tert-butyl-methyl-phosphane borane is reacted with a chiralauxiliary that includes K₂CO₃, DMSO, andN-chloroacetyl-(S)-(−)-4-benzyl-2-oxazolidinone at 55° C. to form amixture of diastereomers(S)-4-benzyl-3-[2-((R)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-oneand(S)-4-benzyl-3-[2-((S)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-onein quantitative yield. These diastereomers can be separated either bycolumn chromatography or via recrystallization.

Each diastereomer can then be reduced with NaBH₄ to remove the chiralauxiliary and form either enantiomer of the alcohol,2-(tert-butyl-methyl-phosphanyl)-ethanol, as shown in FIG. 9. Thealcohol is then reacted with mesylate chloride and pyridine to form thecompound IX. The corresponding enantiomer of compound IX can also beformed by choosing the opposite diastereomer. Compound IX can then bereacted with a mixture of n-butyl lithium and compound VII.Alternatively, compound IX can then be reacted with a mixture of n-butyllithium and t-butylmethylphosphine borane to form Bis-P and a mesoproduct.

The compound with the general Formula Ha can be synthesized via theroute shown in FIG. 10, wherein R is t-butyl, isopropyl, adamantyl,(1,1)-dimethylpropane, (1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁, and Msis mesylate.

The compound with the general Formula Ib can be synthesized via theroute shown in FIG. 11, wherein R is t-butyl, isopropyl, adamantyl,(1,1)-dimethylpropane, (1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁.

Another compound can be synthesized via the route shown in FIG. 12,wherein R is t-butyl, isopropyl, adamantyl, (1,1)-dimethylpropane,(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁, and Ms is mesylate.

Conditions can be used for borane removal or deprotection from thephosphorous atom of borane protected ligands, such as compounds shown inFIG. 9, that do not lead to racemization at the non-C₂-symmetric centerto form compounds I, Ia, Ib, Ic, and IIa. The borane group can beremoved by treating the phosphine borane ligand with HBF₄.Me₂O followedby hydrolysis with K₂CO₃. For example, as shown in FIG. 13, the boranegroups can be removed from an intermediate ligand to form a compoundwith the formula Ia.

Upon completion of borane removal, ligands of the general formulas I canbe bound immediately to rhodium by reacting the ligand with[Rh(norbomadiene)BF₄]₂ to yield a catalyst with the Formula XIa:

wherein:

the achiral phosphorous group includes at least one achiral phosphorousatom having one bond to each of two identical atoms other than thebridge;

the chiral phosphorous group comprises at least one phosphorous atom,wherein the at least one phosphorous atom is chiral or the at least onephosphorous atom is bonded to a chiral substituent; and

a Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl.

suitable transition metal, actinide, or lanthanide and correspondinganion can be used to form the metal/non-C₂ bisphosphine complex shown ascompound XI. For example, the corresponding anion can alternatively bePF₆ ⁻, SbF₆ ⁻, Otf⁻, or ClO₄ ⁻.

Synthesis Route to BisP

Also shown in FIG. 9 is a synthesis method for the formation of BisP.Either enantiomer of compound IX can then easily be converted to eitherenantiomer of BisP, or the ligand Ia, as shown in FIG. 9. The differencein the synthesis of BisP and the ligand Ia is the use of eitherdi-t-butylphosphine borane in the synthesis of ligand la ort-butylmethylphosphine borane in the synthesis of BisP, as thenucleophile that displaces the mesylate in the last step of thesynthesis. In the synthesis of BisP, nucleophilic displacement createsyet another chiral center resulting in a reaction mixture that containsa 50:50 mixture of the chiral ligand and the meso ligand. The mesocompound is easily separated from the chiral compound by columnchromatography. In the case of the di-tert-butylphosphine boraneaddition, no further chiral centers are formed in the reaction so all ofthe material in the reaction mixture after addition is a singleenantiomer chiral compound, Ia.

Asymmetric Transformations with Metal/Non-C₂-Synmetric Ligands

Metal/non-C₂-symmetric ligands of the general Formula XI can be used tocatalyze hydrogenation and other asymmetric reactions. For example,compounds of the general Formula XI can also be used as catalysts intransformations including, but not limited to, hydroformylation, 7-allylpalladium coupling, hydrosilation, hydrocyanation, olefin metathesis,hydroacylation, and isomerization of allylamines.

In the case of asymmetric hydrogenation reactions, themetal/non-C₂-symmetric phospholanes can catalyze various substrates. Forexample, a complex represented by the Formula XIa, wherein the chiralgroup is

and the achiral group is

wherein R is t-butyl, isopropyl, adamantyl, (1,1-dimethylpropane),(1,1-diethylbutane), c-C₅H₉, or c-C₆H₁₁, can be used to catalyzesubstrates, such as enamides, enol esters, and succinates, with thegeneral structural formula

wherein X is N, O, or C; R₁ is an alkyl, a carboxylic acid derivative, acarboxylic ester, or a nitrile; R₂ is an alkyl, an acctyl derivative, ora carboxylic acid; and R₃ is an alkyl or hydrogen, and R₄ is an alkylidentical to the alkyl in R₃ or hydrogen.

Metal/non-C₂-symmetric compounds typically bond to a substrate to becatalyzed through the center, M, which is bound to a phosphorous atom ofthe chiral and achiral phosphorous groups, of a compound with thestructural Formula XIb, its corresponding enantiomer, or solvatesthereof

wherein:

R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing upto about 8 carbon atoms, an aryl group, a substituted aryl group, anaralkyl group, or a ring substituted aralkyl group;

a Bridge is a —(CH₂)_(n)— where n is an integer from 1 to 12; a1,2-divalent phenyl; or a 1,2-divalent substituted phenyl; and

M is a transition metal, an actinide, or a lanthanide.

A solvate of the Formula XIb includes compounds having one or moresolvent molecules bonded to the M center. The solvent molecules include,but are not limited to, MeOH, THF, ethanol, isopropanol, acetonitrile,methylene chloride, benzene, toluene, water, ethyl acetate, dioxane,carbon tetrachloride, DMSO, DMF, DMF/water mixtures, supercriticalcarbon dioxide, alcohol/water mixtures or any other suitable solvent.

NON-C₂-SYMMETRIC LIGAND AND CATALYSTS GENERAL PROCEDURES

Materials. THF was distilled from sodium prior to use or THF (anhydrous,99.9%) was used as needed from Aldrich Sure-Seal bottles supplied byAldrich Chemical Company. Dichloromethane (anhydrous, 99.8%) and diethylether (anhydrous, 99.8%) were used as needed from Aldrich Sure-Scalbottles supplied by Aldrich Chemical Company. Methyl sulfoxide (DMSO,A.C.S. reagent, 99.9%), sodium borohydride (995), methanesulfonylchloride (99.5%+), tert-butylmagnesium chloride (2.0 M diethyl ether),borane-methylsulfide complex (approximately 10-10.2 M), phosphoroustrichloride (98%), lithium aluminum hydride (powder, 95%), and n-BuLi(2.5M hexanes) were obtained from Aldrich Chemical Company.N-chloroacetyl-(S)-(−)-4-benzyl-2-oxazolidinone was prepared accordingto literature procedures described in Tang, J. S., Verkade J. G. J. Org.Chem. 1996;61:8750-8754.

Nuclear Magnetic Resonance. 400 MHz ¹H NMR, 100 MHz ¹³C NMR, and 162 MHz³¹P NMR spectra were obtained on “Barton”—a Varian Unity+400 (Inova400after Aug. 15, 2000) spectrometer equipped with an Auto Switchable4-Nuclei PFG probe, two RF channels, and a SMS-100 sample changer byZymark. Spectra were generally acquired near room temperature (21° C.),and standard autolock, autoshim, and autogain routines were employed.Samples are usually spun at 20 Hz for 1D experiments. ¹H NMR spectrawere acquired using 45-degree tip angle pulses, 1.0 second recycledelay, and 16 scans at a resolution of 0.25 Hz/point. The acquisitionwindow was typically 8000 Hz from +18 to −2 ppm (Reference TMS @0 ppm),and processing was with 0.2 Hz line broadening. Typical acquisition timeis 80 seconds. Regular ¹³C NMR spectra were acquired using 45-degree tipangle pulses, 2.0 second recycle delay, and 2048 scans at a resolutionof 1 Hz/point. Spectral width was typically 25 KHz from +235 to −15 ppm(Reference TMS @0 ppm). Proton decoupling was applied continuously, and2 Hz line broadening was applied during processing. Typical acquisitiontime is 102 minutes. 31 P NMR spectra were acquired using 45-degree tipangle pulses, 1.0 second recycle delay, and 64 scans at a resolution of2 Hz/point. Spectral width was typically 48 KHz from +200 to −100 ppm(Reference 85% Phosphoric Acid (0 ppm). Proton decoupling was appliedcontinuously, and 2 Hz line broadening was applied during processing.Typical acquisition time is 1.5 minutes.

High Performance Liquid Chromatography. High Performance LiquidChromatography (HPLC) was performed on a series 1100 Hewlett Packard(now Agilent Technologies) instrument equipped with a manual injector,quaternary pump, and a UV detector. The LC was PC controlled using HPhesitation Plus Software. Reverse phase HPLC was performed with a150×4.6 mm BDS-Hypersil-C18 column supplied by Keystone ScientificIncorporated. Reverse phase chiral HPLC was performed using a ChiracelOJ-R column supplied by Chiral Technologies. Normal Phase chiral HPLCwas performed a Chiracel OD-H column supplied by Chiral Technologies.

EXAMPLE 1 Synthesis of di-tert-Butyl-phosphane Borane

PCl₃ (3.94 g, 2.5 ml, 0.029 mole) was dissolved in 75 mL anhydrous THFin a 250-mL round bottom flask under N₂ and then cooled to 0° C. with anice bath. The tert-butylmagnesium chloride (29 mL, 0.058 mole, 2.0 M indiethyl ether) was added dropwise via syringe, and then the reaction wasstirred 1.5 hours at 0° C. Lithium aluminum hydride (1.1 g, 0.029 mole)was then delivered to the reaction as a dry powder in portions over 20minutes. After the addition, borane methylsulfide (2.9 mL, 0.029 mole10.0 M solution) was delivered via syringe. After stirring overnight,the reaction was cooled to 0° C. and then quenched cautiously with 150mL 1N HCl. The reaction mixture was poured into a separatory funnel, andthe organic layer was separated. The aqueous layer was extracted with2×100 mL Et₂O and then the combined organics were dried over MgSO₄. Thevolatiles were then removed on a rotary evaporator at reduced pressure.The crude product was passed through a plug of silica gel using 3% ethylacetate/hexane to yield the title compound with sufficient purity forsubsequent chemistry. ¹H NMR (400 MHz, CDCl₃) δ 0.0-0.9 (m, 3H), 1.28(d, J_(H-P)=13.4 Hz, 18H), 3.65 (dm, J_(H-P)=351.2 Hz, 1H); ³¹P NMR (162MHz, CDCl₃) δ 49.0 ppm (br m).

EXAMPLE 2 Synthesis of tert-Butyl-methyl-phosphane Borane

Dichloromethylphosphine (25 g, 0.214 mole) was poured out of an ampuleinto a 3-neck 1000-mL flask equipped with an addition funnel whileblowing N₂ through the flask. Nitrogen degassed anhydrous Et₂O (350 mL)was immediately poured into the flask and then the flask was sealed witha septum. The solution was cooled to 0C and then borane methylsulfide(21.4 mL, 0.214 moles, 10.0 M solution) was delivered to the solutionvia syringe. After stirring for 20 minutes, tert-butylmagnesium chloride(107 mL, 0.214 mole, 2.0 M in ethyl ether) was delivered via theaddition funnel over a period of one hour while maintaining the reactionsolution at 0° C. During the addition, a white precipitate formed whichpersisted during stirring for 45 minutes after the addition. Lithiumaluminum hydride was then delivered to the reaction as a dry powder inportions over 20 minutes while maintaining the reaction temperature at0° C. After the addition the reaction was warmed to room temperature andthen stirred overnight. It was then cooled to 0° C. and quenchedcautiously with 400 mL 1N HCl. The organic layer was separated, and thenthe aqueous layer was extracted with 100 mL Et₂O. The combined organicswere combined and washed with 1N HCl and brine and then dried overMgSO₄. Removal of the solvent in vacuo yielded 23.4 g/93% of the titlecompound with sufficient purity for subsequent chemistry. ¹H NMR (400MHz, CDCl₃) δ 0-0.8 (m, 3H), 1.17 (d, J_(H-P)=14.65 Hz, 9H), 1.28 (dd,J=4.64 Hz, J=5.86 Hz, 3H), 4.38 (dm, J_(H-P)=355.2 Hz, 1H); ³¹P NMR (162MHz, CDCl₃) δ 12.0 (br m).

EXAMPLE 3 Synthesis of(S)-4-Benzyl-3-[2-((R)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-oneand(S)-4-Benzyl-3-[2-((S)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-one

N-Chloroacetyl-(S)-(−)-4-benzyl-2-oxazolidinone (6.39 g, 0.0254 mole)was placed in a 250-mL round bottom flask.(+/−)-tert-butyl-methyl-phosphane borane was added to the flask alongwith 75 mL DMSO. Potassium carbonate (17.5 g, 0.127 mole) was added inone portion and the reaction was placed under N₂. The reaction washeated to 55° C. in an oil bath and stirred for one hour. The resultingsolution was red and K₂CO₃ was not completely dissolved in solution. Thereaction was cooled to room temperature and then was poured into 500 mL1N HCl which had been chilled to 0° C. Ethyl acetate (300 mL) was addedand the biphasic solution was shaken briskly in a separatory funnel. Theorganic layer was separated and then the aqueous layer was extractedwith 100 mL ethyl acetate. The combined organic layers were then washedsuccessively with distilled water and then brine. The organic layer wasdried over MgSO₄ and the solvent was removed in vacuo. The crude whiteoily product was triturated with 2×75 mL warm hexane to remove excessphosphine and then the resulting white solid was dissolved in 30 mL hotethyl acetate and allowed to cool to room temperature. Upon cooling,crystals formed. The crystals were collected on filter paper and thenwashed with 30 mL hexane. Crystals then formed in the filtrate. Thediastereomeric ratio of the crystals on the filter paper was 92 ((S,R)isomer):8 ((S,S) isomer) and they weighed 1.17 g. After collecting thecrystals from the filtrate on filter paper and washing with hexane itwas found that the diastereomeric ratio of these crystals was 8 ((S,R)isomer):92 ((S,S) isomer) and then weighed 1.20 g. Successiverecrystallization of both diastereomers with EtOAc/hexane yieldedcompounds with diastereomeric purity exceeding 99%. It is also possibleto separate the (S,R) and (S,S) diastereomers via column chromatographyover silica gel (15%/ ethyl acetate, hexane) collecting the (S,R) isomerat R_(f)=0.38 and the (S,S) isomer at R_(f)=0.28. Stereochemistry of thechirogenic phosphorous atom of each diastereomer was assigned by analogyusing a comparison of elution orders of the enantiomers of Bis-P boranesmade from this route with the elution orders of Bis-P boranes describedin Imamoto, T. et al., supra., 1998.

(S)-4-Benzyl-3-[2-((R)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ −0.2-0.8 (m, 3H), 1.22 (d, J_(H-P)=14.7 Hz,9H), 1.43 (d, J_(H-P=)9.89 Hz, 3H), 2.80 (m, 2H), 3.36 (dd, J=3.38 Hz,J=13.5 Hz, 1H), 4.15 (dd, J=2.17 Hz, J=8.92 Hz, 1H), 4.26 (dd, J=8.68Hz, J=8.68 Hz, 1H), 4.34 (dd, J=9.16 Hz, J=12.18 Hz, 1H), 4.68 (m, 1H),7.22-7.36 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 6.6 (d, J_(C-P)=33.6 Hz),24.9, 28.1 (d, J_(C-P)=20.6 Hz), 38.2, 56.1, 66.3, 127.4, 129.2 (d,J_(C-P)=46.5 Hz), 135.4, 154.0, 167.5; ³¹P NMR (162 MHz, CDCl₃) δ 27.8(br m).

(S)-4-Benzyl-3-[2-((S)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-one:

¹H NMR (400 MHz, CDCl₃) δ −0.2-0.8 (m, 3H), 1.24 (d, J_(H-P)=14.47 Hz,9H), 1.45 (d, J_(H-P)=9.89 Hz, 3H), 2.76 (dd, J=10.6 Hz, J=10.6 Hz, 1H),3.21 (dd, J=13.3 Hz, J=13.3 Hz, 1H), 3.50 (dd, J=3.6 Hz, J=13.8 Hz, 1H),3.94 (dd, J=10.1 Hz, J=12.8 Hz, 1H), 4.14-4.22 (m, 2H), 4.71 (m, 1H),7.23-7.28 (m, 3H), 7.31-7.35 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 8.0 (d,J_(C-P)=30 Hz), 24.9, 27.9 (d, J_(C-P)=22 Hz), 29.0 (d, J_(C-P)=30 Hz),38.0, 55.8, 66.2, 127.3, 129.0, 136.0, 154.0, 168.0; ³¹P NMR (162 MHz,CDCl₃) δ 31.2 (br m).

EXAMPLE 4 Synthesis of (R)-2-(tert-Butyl-methyl-phosphanyl)-ethanol

(S)-4-Benzyl-3-[2-((R)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-onewas dissolved in 60 mL anhydrous THF and then cooled to 0° C. in a250-mL round bottom flask. NaBH₄ was added in one portion along with 15mL distilled water. The reaction foamed after addition and when foamingwas complete the reaction was warmed to room temperature and stirredovernight whereupon the reaction was quenched with 50 mL 2N HCl. Thereaction was poured into a separatory funnel and 30 mL ethyl acetate wasadded. The organic layer was separated after shaking and then theaqueous layer was extracted with 2×50 mL ethyl acetate. The organiclayers were combined and dried over MgSO₄ and then the volatiles wereremoved in vacuo. The crude product was passed through a plug of silicagel using 25% ethyl acetate/hexane and after removing the volatiles invacuo, 1.651 g/97.1% of the title compound was isolated. The (S) isomercan be synthesized via the same procedure starting from(S)-4-benzyl-3-[2-((S)-tert-butyl-methyl-phosphanyl)-ethanoyl]-oxazolidin-2-one.

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J_(H-P)=13.74 Hz, 9H), 1.25 (d,J_(H-P)=9.9 Hz, 3H), 1.81-1.92 (m, 2H), 2.42 (br s, 1H); 3.92 (dt,J=15.2 Hz, J=6.3 Hz, 2H); ¹³C (100 MHz, CDCl₃) δ 6.3 (d, J_(C-P)=35.1Hz), 24.6 (d, J=32.1 Hz), 24.9, 27.2 (d, J_(C-P)=35.1 Hz), 57.8; ³¹P(162 MHz, CDCl₃) δ 23.2 (br m).

EXAMPLE 5 Synthesis of Methanesulfonic Acid2-((R)-tert-Butyl-methyl-phosphanyl Borane)-ethyl Ester

The (R)-2-(tert-butyl-methyl-phosphanyl)-ethanol (1 27 g, 6.957 mmole)was dissolved in 10 mL pyridine and cooled to 0° C. Methanesulfonylchloride (0.59 mL, 7.65 mmole) was added dropwise via syringe. After onehour white salts had precipitated from the reaction solution. Thereaction was then quenched with 50 mL distilled water. The reactionmixture was poured into a separatory funnel and the aqueous layer wasextracted with 2×50 mL Et₂O. The combined organics were dried over MgSO₄and then the volatiles were removed in vacuo yielding 1.553 g/93% of themesylate product which was subjected to no further purification. The (S)isomer can be synthesized via the same procedure starting from(S)-2-(tert-butyl-methyl-phosphanyl)-ethanol. ¹H NMR (400 MHz, CDCl₃) δ0.0-0.8 (br m), 1.17 (d, J_(H-P)=14.2 Hz, 9H), 1.30 (d, J_(H-P)=9.9 Hz,3H), 1.90 (br s, 1H), 2.08 (dt, J=10.9 Hz, J=7.5 Hz, 2H), 3.05 (s, 3H),4.41-4.59 (m, 2H); ³1P NMR (162 MHz, CDCl₃) δ 25.5 (br m).

EXAMPLE 6 Synthesis of (R,R)-1,2-Bis(tert-butyl-methyl-phosphanylBorane) Ethane

Methanesulfonic acid 2-((R)-tert-butyl-methyl-phosphanyl borane)-ethylester (536 mg, 2.232 mmole) was dissolved in 7 mL anhydrous THF in a50-mL round bottom flask under N₂. The solution was cooled to −78° C.with a dry ice/acetone bath with stirring. In a separate 25-mL roundbottom flask was dissolved (+/−)-tert-butyl-methyl-phosphane borane.This solution was placed under N₂ and then cooled to −78° C. n-BuLi(1.07 mL, 2.678 mmole, 2.5 M in hexane) was added dropwise via syringeto the (+/−)-tert-butyl-methyl-phosphane borane solution. The reactionwas stirred for 20 minutes at −78° C. and then the solution was taken upin a syringe and delivered to the mesylate solution over 30 seconds. Thereaction was stirred 20 minutes at −78° C. and then warmed to roomtemperature and stirred overnight. TLC (25% ethyl acetate/hexane) showedtwo products with R_(f)=0.49 (meso Bis-P) and R_(f)=0.38 (Bis-P). Columnchromatography over silica gel eluting first with 7% ethylacetate/hexane and increasing the gradient eventually to 25% ethylacetate/hexane yielded 130 mg/44.5% meso compound and 147 mg/50.3% Bis-P(>99% e.e. of the (R,R) isomer). The (S,S) isomer can be synthesized viathe same procedure starting from Methanesulfonic acid2-((S)-tert-butyl-methyl-phosphanyl borane)-ethyl ester. Enantiomericpurity was determined by chiral HPLC using a Chiracel OD-H column (10mm, 4.6×250 mm), mobile phase Hexanes:IPA:TFA 95:5:0.1, flow rate of 0.5mL/min, and RI detection at 1/16 range. The (S,S) isomer was observed at17.9 minutes and the (R,R) isomer was observed at 12.0 minutes. Spectraldata was identical to that described in Imamoto T., et al., supra.,1998.

EXAMPLE 7 Synthesis of 1-(di-tert-Butyl-phosphanylBorane)-((R)-2-tert-butyl-methyl-phosphanyl Borane) Ethane

Methanesulfonic acid 2-((R)-tert-butyl-methyl-phosphanyl borane)-ethylester (660 mg, 2.75 mmole) was dissolved in 7 mL anhydrous THF in a50-mL round bottom flask under N₂. The solution was cooled to −78° C.with a dry ice/acetone bath. In a separate 25-mL round bottom flask wasdissolved di-tert-butyl-phosphane borane (528 mg, 3.30 mmole). Thissolution was placed under N₂ and then cooled to −78° C. n-BuLi (1.32 mL,3.30 mmole, 2.5 M in hexane) was added dropwise via syringe to thedi-tert-butyl-phosphane borane solution. The reaction was stirred for 20minutes at −78° C. and then the solution was taken up in a syringe anddelivered to the mesylate solution over 30 seconds. The reaction wasstirred 20 minutes at −78° C. and then warmed to room temperature andstirred overnight. TLC (25% ethyl acetate/hexane) showed title productwith R_(f)=0.53. Column chromatography over silica gel (10% ethylacetate/hexane) yielded 370 mg/44% of the title compound. The (S) isomercan be synthesized via the same procedure starting from Methanesulfonicacid 2-((S)-tert-butyl-methyl-phosphanyl borane)-ethyl ester. ¹H NMR(400 MHz, CDCl₃) δ −0.2-0.8 (br m, 3H), 1.05-1.30 (br m, 30H), 1.50-1.70(br m, 2H), 1.75-2.05 (br m, 2H), ³¹P NMR (162 MHz, CDCl₃) δ 30.0 (brm), 47.0 (br, m).

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds.

The present invention should not be considered limited to the particularexamples described above, but rather should be understood to cover allaspects of the invention as fairly set out in the attached claims.Various modifications, equivalent processes, as well as numerousstructures to which the present invention may be applicable will bereadily apparent to those of skill in the art to which the presentinvention is directed upon review of the instant specification.

What is claimed is:
 1. A non-C₂ symmetric bisphosphine ligand havingstructural formula:

wherein the bridge is a 1,2-divalent phenyl, a 1,2-divalent substitutedphenyl, or a —(CH₂)_(n)— in which n is an integer from 1 to 12; theachiral phosphine group is

in which R is t-butyl, isopropyl, adamantyl, 1,1-dimethylpropane,1,1-diethylbutane, or c-C₅H₉; and the chiral phosphine group includes athree-coordinated phosphorous atom which is bonded to the bridge and totwo carbon atoms, the two carbon atoms and the phosphorus atom not beingpart of a ring system.
 2. The non-C₂ symmetric bisphosphine ligand ofclaim 1, wherein the bridge is —(CH₂)_(n)— and n is an integer from 1 to12.
 3. The non-C₂ symmetric bisphosphine ligand of claim 1, wherein R ist-butyl.
 4. The non-C₂ symmetric bisphosphine ligand of claim 2, whereinn is an integer from 1 to
 2. 5. The non-C₂ symmetric bisphosphine ligandof claim 4, wherein R is t-butyl.
 6. A non-C₂ symmetric bisphosphineligand having structural formula:

wherein the bridge is a 1,2-divalent phenyl, a 1,2-divalent substitutedphenyl, or a —(CH₂)_(n)— in which n is an integer from 1 to 12; theachiral phosphine group includes a three-coordinated, achiralphosphorous atom which is bonded to the bridge and to two carbon atoms,the two carbon atoms and the phosphorus atom not being part of a ringsystem; and the chiral phosphine group is

or corresponding enantiomers, in which R is t-butyl, isopropyl,1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁.
 7. Thenon-C₂ symmetric bisphosphine ligand of claim 6 wherein the bridge is—(CH₂)_(n)— and n is an integer from 1 to
 12. 8. The non-C₂ symmetricbisphosphine ligand of claim 7 wherein the chiral phosphine group is

or its corresponding enantiomer and R is t-butyl, isopropyl,1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁.
 9. Thenon-C₂ symmetric bisphosphine ligand of claim 8, wherein R is t-butyl.10. The non-C₂ symmetric bisphosphine ligand of claim 7, wherein n is aninteger from 1 to
 2. 11. The non-C₂ symmetric bisphosphine ligand ofclaim 10 wherein the chiral phosphine group is

or its corresponding enantiomer and R is t-butyl, isopropyl,1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁.
 12. Thenon-C₂ symmetric bisphosphine ligand of claim 11 wherein R is t-butyl.13. A compound having the structural formula:

or its corresponding enantiomer, in which R₁ is t-butyl, isopropyl,adamantyl, 1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁,and R₂ is t-butyl, isopropyl, 1,1-dimethylpropane, 1,1-diethylbutane,c-C₅H₉ or c-C₆H₁₁.
 14. A compound having the structural formula:

or its corresponding enantiomer, in which R₁ t-butyl, isopropyl,adamantyl, 1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁.15. A compound having the structural formula:

or its corresponding enantiomer.
 16. A non-C₂ symmetric bisphosphineligand having structural formula:

wherein the achiral phosphine group is

in which R is t-butyl, isopropyl, adamantyl, 1,1-dimethylpropane,1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁; the chiral phosphine groupincludes a three-coordinated phosphorous atom which is bonded to thebridge and to two carbon atoms, the two carbon atoms and the phosphorusatom not being part of a ring system; and each Y is independentlyhalogen, alkyl, alkoxy, aryl, aryloxy, nitro, amino, vinyl, substitutedvinyl, alkynyl, or sulfonic acid, and n is an integer from 0 to
 4. 17. Anon-C₂ symmetric bisphosphine ligand having structural formula:

wherein the achiral phosphine group includes a three-coordinated,achiral phosphorous atom which is bonded to the bridge and to two carbonatoms, the two carbon atoms and the phosphorus atom not being part of aring system; the chiral phosphine group is

or corresponding enantiomers, in which R is t-butyl, isopropyl,adamantyl, 1,1-dimethylpropane, 1,1-diethylbutane, c-C₅H₉, or c-C₆H₁₁;and each Y is independently halogen, alkyl, alkoxy, aryl, aryloxy,nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid and nis an integer from 0 to 4.